U.S. patent number 4,948,588 [Application Number 07/361,489] was granted by the patent office on 1990-08-14 for percutaneous absorption accelerator and preparation containing same.
This patent grant is currently assigned to Kao Corporation. Invention is credited to Yasuteru Eguchi, Takeshi Inoue, Tetsuro Kamiya, Kaoru Tsujii, Hidenori Yorozu.
United States Patent |
4,948,588 |
Kamiya , et al. |
August 14, 1990 |
Percutaneous absorption accelerator and preparation containing
same
Abstract
A percutaneous absorption accelerator and a percutaneous
absorbent preparation containing the same and, more particularly, a
percutaneous absorption accelerator containing either derivatives
of specific glycerols or polyglycerols and alcohols as effective
components and a percutaneous absorbent preparation containing the
percutaneous absorption accelerators and pharmaceutically effective
components.
Inventors: |
Kamiya; Tetsuro (Tochigi,
JP), Inoue; Takeshi (Tochigi, JP), Yorozu;
Hidenori (Tochigi, JP), Eguchi; Yasuteru
(Tochigi, JP), Tsujii; Kaoru (Tochigi,
JP) |
Assignee: |
Kao Corporation (Tokyo,
JP)
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Family
ID: |
13775227 |
Appl.
No.: |
07/361,489 |
Filed: |
June 2, 1989 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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227777 |
Aug 3, 1988 |
4859696 |
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47513 |
May 6, 1987 |
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726320 |
Apr 23, 1985 |
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Foreign Application Priority Data
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Apr 23, 1984 [JP] |
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59-82464 |
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Current U.S.
Class: |
424/436; 424/433;
424/434; 424/435; 424/443; 424/444; 424/449; 424/45; 424/47;
514/165; 514/5.9; 514/946; 514/947 |
Current CPC
Class: |
A61K
9/0014 (20130101); A61K 47/10 (20130101); Y10S
514/969 (20130101); Y10S 514/946 (20130101); Y10S
514/947 (20130101) |
Current International
Class: |
A61K
47/10 (20060101); A61K 009/02 () |
Field of
Search: |
;424/433,434,435,436,449
;514/3,4,165,946,947 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1142969 |
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Mar 1983 |
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CA |
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0071019 |
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Feb 1983 |
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EP |
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2069334 |
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Aug 1981 |
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GB |
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1539625 |
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Jan 1989 |
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GB |
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Other References
Holford et al., "Transdermal Systems in Principle and Practice",
Current Therapeutics, Jan. 1984, leading article..
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Spear; James M.
Attorney, Agent or Firm: Birch, Stewart, Kolasch &
Birch
Parent Case Text
This application is a divisional of copending application Ser. No.
227,777 filed Aug. 3, 1988 now U.S. Pat. No. 4,559,696, which is a
continuation of Ser. No. 047,513 filed on May 6, 1987, now
abandoned, which is a continuation of Ser. No. 726,320 filed on
Apr. 23, 1985, now abandoned.
Claims
What is claimed is:
1. A percutaneous absorbent preparation for transdermal or
transmucosal absorption of a pharmaceutically active substance,
comprising:
an effective amount of pharmacopeial aspirin, or insulin; and
an absorption accelerator selected from the group consisting of
1-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-dodecyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-tetradecyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-hexadecyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-octadecenyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-octadecenyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-methyl-branched isostearyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-octyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-dodecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-dodecyl-2-O-n-butyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-dodecyl-2-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-tetradecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-hexadecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-octadecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-octadecenyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-octadecenyl-2-O-n-butyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-methyl-branched
isostearyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-methyl-branched
isostearyl-2-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol;
1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol;
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol;
1-O-n-dodecyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol;
1-O-n-dodecyl-3-O-n-octyl-2-O-2',3'-dihydroxypropylglycerol;
1-O-n-tetradecyl-3-methyl-2-O-2',3'-dihydroxypropylglycerol;
1-O-n-hexadecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol;
1-O-n-octadecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol;
1-O-n-octadecenyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol;
1-O-n-octadecenyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol;
1-O-methyl-branched
isostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol;
1-O-methyl-branched
isostearyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol; and
1-O-methyl-branched
isostearyl-3-O-n-octyl-2-O-2',3'-dihydroxypropylglycerol.
2. The preparation of claim 1, which is in the form of a liquid, a
lotion, an ointment, a cream, a gel, a sol, an aerosol, a
cataplasm, a plaster, or a tape preparation.
3. The preparation of claim 2, which is in the form of a
suppository comprising:
(a) pharmacopeial aspirin;
(b) 1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol;
and
(c) a medium chain fatty acid triglyceride.
4. The preparation of claim 2, which is in the form of a
suppository comprising:
(a) pharmacopeial aspirin;
(b) 1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol;
and
(c) a medium chain fatty acid triglyceride.
5. The preparation of claim 2, which is in the form of a
suppository comprising:
(a) a solution of 100 IU of insulin in 0.5 ml of a 6% aqueous
acetic acid solution;
(b) 1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol;
and
(c) a medium chain fatty acid triglyceride.
6. The preparation of claim 2, which is in the form of a spraying
agent for nasal use, comprising:
(a) a solution of 1000 IU of insulin in 2.0 ml of a 6% aqueous
acetic acid solution;
(b) 1-O-methyl-branched
isostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol;
(c) ethanol; and
(d) physiological saline solution.
Description
BACKGROUND OF THE INVENTION
The present invention relates to a percutaneous absorption
accelerator and a percutaneous absorbent preparation containing the
same, and more particularly, to a percutaneous absorption
accelerator containing ether derivatives of specific glycerols or
polyglycerols and alcohols as the active ingredients and
percutaneous absorbent accelerators and pharmaceutically effective
components.
As methods for administration of drugs, oral, rectal,
intracutaneous administration, and so forth have been generally
adopted. Among these, oral administration has been widely employed.
However, in the case of oral administration, certain difficulties
have been encountered with side effects such as gastrointestinal
disturbances, anorexia, vomitting, and abdominal pain; in addition,
it is necessary in most cases, to administer large quantities of
these drugs. In recent years, preparations for percutaneous
administration have been developed. Some have been for commerial
use, in hopes that the side effects would be minimized and the
desired pharmacological effects would occur more safely. In many
cases, however, percutaneous absorbability of pharmaceutically
effective components in such preparations are unsatisfactory and
the purposes have been satisfactorily achieved only with
difficulty. Namely, skin, and its keratin layer (which constitutes
the outermost layer), functions physiologically and acts as a
protective wall against permeation of substances into the body. In
many cases, it is difficult for a base alone, used for conventional
topical agents, to attain percutaneous absorption sufficient for
the pharmaceutically components formulated therein to be effective.
For this reason, a device is necessary to control the permeability
of drugs through the keratin layer of the skin and enhance the
percutaneous absorption of drugs.
In addition, for accelerating absorption of pharmacologically
active substances from the mucous portions of the human body, such
as the mucous membrane of the eye, nasal mucous membrane, buccal
mucous membrane, vaginal mucous membrane, rectal mucous membrane,
improvement of the preparation form, improvement of bases,
formulation of compounds having an absorption acceleration effect,
and the like have been made. Among them, the improvement of the
preparation form and the improvement of bases are possible to a
certain extent; however, epoch-making improvement is not expected
and the target of research has been focused on the search for and
application of compounds having an absorption accelerating
effect.
For such purposes, it has generally been known to formulate a so
called percutaneous absorption accelerator in a base. As such
absorption accelerators, there are known dimethyl sulfoxide; amide
compounds such as dimethyl acetamide, dimethylformamide, and
N,N-diethyl-m-toluamide, azacycloalkan-2-one derivatives, such as
1-dodecylazacyclo-heptan-2-one; esters of alcohol and carboxylic
acids, such as isopropyl myristate, isopropyl palmitate, diethyl
sebacate, and diisopropyl adipate; and
crotonyl-N-ethyl-o-toluidine. However, these absorption
accelerators have been found to be unsatisfactory in their
absorption accelerating effect and, in many cases, practical
pharmacological effects cannot be obtained. Moreover, these
pharmacological effects cannot be obtained. In addition, these
absorption accelerators involve problems in practical use because
the absorption accelerators themselves show irritation to the skin
and corrode synthetic resins due to their property as potent
solvents to dissolve irritative substances, and sensitized
substances out of containers for drugs, clothes, and accessories,
so that general adaptation and use are restricted.
SUMMARY OF THE INVENTION
Therefore, in accordance with the present invention it has been
found that by formulating specific ether derivatives of glycerols
or polyglycerols as percutaneous absorption accelerators in a base,
percutaneous absorption of pharmaceutically effective components
can be markedly increased and the pharmacological effects of the
pharmaceutically effective components can be demonstrated
effectively and safely.
DETAILED DESCRIPTION
Namely, the present invention provides percutaneous absorption
accelerators comprising ether compounds of glycerols or
polyglycerols and alcohols (hereafter simply referred to as "ether
derivatives") as essential components and, percutaneous absorbent
preparations containing pharmaceutically effective components and
the percutaneous absorption accelerators. The term percutaneous
absorption in the present invention means the absorption through a
mucosal portion of the human body, such as the mucous membrane of
the eye, nasal mucous membrane, buccal mucous membrane, vaginal
mucous membrane, rectal mucous membrane, and the like in addition
to the topical percutaneous absorption through the keratin layer of
the skin.
The ether derivatives used in the present invention are obtained by
reacting alcohols with glycerols or polyglycerols derived therefrom
in a conventional manner. Specific examples of alcohols which are
used include straight chain type aliphatic alcohols, such as methyl
alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, octyl
alcohol, decyl alcohol, dodecyl alcohol, hexadecyl alcohol,
octadecyl alcohol, and octadecanyl (oleyl) alcohol; branched type
aliphatic primary alcohols, such as isopropyl alcohol, isobutyl
alcohol, 2-ethylhexyl alcohol, 2-heptylundecyl alcohol,
2-(1,3,3-trimethylbutyl) octyl alcohol, 2-decyltetradecyl alcohol,
2-dodecylhexadecyl alcohol, 2-tetradecyloctadecyl alcohol,
5,7,7-trimethyl-2-(1,3,3-trimethylbutyl)octyl alcohol and
methyl-branced isostearyl alcohols represented by the following
formula: ##STR1## wherein p represents an integer of 4 to 10; and q
represents an integer of 5 to 11, and p+q represents 11 to 17 and
has a distribution which is optimum when p is 17 and q is 18;
secondary alcohols, such as sec-octyl alcohol, sec-decyl alcohol,
and sec-dodecyl alcohol; tertiary alcohols, such as t-octyl
alcohol, and t-dodecyl alcohol; alicyclic alcohols such as
cyclohexyl alcohol, and cyclopentyl alcohol; alkylphenols, such as
octylphenol, and nonylphenol.
Of the other derivatives used in the present invention preferred
are those represented by the following formula (I) or (II):
##STR2## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 (n numbers
of R.sub.4 may be the same or different) each represents a
hydrogen, a saturated or unsaturated straight or branched aliphatic
hydrocarbon group or aromatic hydrocarbon group having 1 to 24
carbon atoms, provided that R.sub.1, R.sub.2, R.sub.3 and R.sub.4
(n times repeated) are not all hydrogen; and n represents an
integer of 0 to 60.
In the ether derivatives represented by the formula (I) or (II), it
is preferred that R.sub.1 to R.sub.4 each be an aliphatic
hydrocarbon having 1 to 18 carbon atoms and the total carbon atoms
of R.sub.1 to R.sub.4 be 4 to 36, preferably 8 to 12. Further, it
is preferred that n be a number of 0 to 60. Particularly preferred
are those wherein n is 0 to 20, and preferably 0 to 10. A more
preferred combination of R.sub.1 to R.sub.4 and n is the
combination wherein n is 0 or 1 and the total carbon atoms of
R.sub.1 to R.sub.4 are 4 to 36, particularly the combination in
which n is 1 and the total carbon atoms of R.sub.1 to R.sub.4 is 8
to 22.
Of the ether derivatives (I) or (II), preferred examples include
straight chain primary alkyl glycerols, such as
1-O-n-octylglycerol, 1-O-n-decylglycerol, 1-O-n-dodecylglycerol,
1-O-n-tetradecylglycerol, 1-O-n-hexadecylglycerol,
1-O-n-octadecylglycerol, and 1-O-n-octadecenylglycerol branched
chain primary alkylglycerols, such as 1-O-2-ethylhexylglycerol,
1-O-2-hexyldecylglycerol, 1-O-2-heptylundecylglycerol,
1-O-2-octyldodecylglycerol,
1-O-2-(1,3,3-trimethylbutyl)octylglycerol,
1-O-5,7,7-trimethyl-2-(1,3,3-trimethylbutyl)octylglycerol, and
1-O-methyl-branched isostearylglycerols secondary alkylglycerols,
such as 1-O-sec-octylglycerol, 1-O-sec-decylglycerol, and
1-O-sec-dodecylglycerol; 1-O-alkylglycerols, such as
1-O-t-octylglycerol, 1-O-t-dodecylglycerol;
1-O-alkyl-3-O-2',3'-dihydroxypropylglycerols such as
1-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-dodecyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-tetradecyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-hexadecyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-octadecyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-octadecenyl-3-O-2',3'-dihydroxypropylglycerol, and
1-O-methyl-branched isostearyl-3-O-2',3'-dihydroxypropylglycerol;
1,2-di-O-alkyl-3-O-2',3'-dihydroxypropylglycerols, such as
1-O-n-octyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-dodecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-dodecyl-2-O-n-butyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-dodecyl-2-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-tetradecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-hexadecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-octadecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-octadecenyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-n-octadecenyl-2-O-n-butyl-3-O-2',3'-dihydroxypropylglycerol,
1-O-methyl-branched
isostearyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol, and
1-O-methyl-branched
isostearyl-2-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol;
1,3-di-O-alkyl-2-O-2',3'-dihydroxypropylglycerols, such as
1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,
1-O-n-dodecyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol,
1-O-n-dodecyl-3-O-n-octyl-2-O-2',3'-dihydroxypropylglycerol,
1-O-n-tetradecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,
1-O-n-hexadecyl-3-O-methyl-2-O- 2',3'-dihydroxypropylglycerol,
1-O-n-octadecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,
1-O-n-octadecenyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,
1-O-n-octadecenyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol,
1-O-methyl-branched
isostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,
1-O-methyl-branched
isostearyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol, and
1-O-methyl-branched
isostearyl-3-O-n-octyl-2-O-2',3'-dihydroxypropylglycerol. The ether
derivatives of glycerol or polyglycerol with these alcohols have
extremely low toxicity in LD.sub.50 of 5000 mg/kg or more.
The percutaneous absorption accelerator of the present invention is
prepared using the ether derivative of glycerol or polyglycerol
with alcohols as it is, or by dissolving, dispersing or suspending
the ether derivative of glycerol or polyglycerol with alcohols in a
suitable solvent such as water, ethanol, propylene glycol,
triacetin, or the like. Further, the percutaneous absorption
accelerator of the present invention may be formulated, if
necessary, with known compounds having a percutaneously absorbing
property, for example, dimethylsulfoxide, dimethylacetamide,
dimethylformamide, N,N-diethyl-m-toluamide, azacycloalkan-2-one
derivatives, such as 1-dodecylazacycloheptan-2-one, esters of
alcohols and carboxylic acids, such as isopropyl myristate,
isopropyl palmitate, diethyl sebacate, and diisopropyl adipate,
crotonyl-N-ethyl-o-toluidine, and the like.
The percutaneous absorbent preparation of the present invention may
be formulated by incorporating various pharmaceutically effective
components with the percutaneous absorption accelerator. The
percutaneous absorption accelerator can be advantageously used for
many preparations of topical agents which are expected to exhibit
the pharmacological effect upon application to skin, hair, nails,
and the like to be absorbed for example, from a liquid spraying
agent, a lotion, an ointment, a cream, a gel, a sol, an aerosol, a
cataplasm, a plaster, a tape preparation, and the like.
Further, in a transmucosal administration, the percutaneous
absorbent preparation of the present invention is prepared using
the above-mentioned transmucosal absorption accelerator either as
it is, or, by formulating the same in various forms of preparations
for transmucosal administration, for example, suppositories for
rectal and vaginal administration, an ointment, a soft gelatin
capsule, a buccal tablet, a perlingual tablet, a nose drop, or a
spraying agent for nasal mucous membrane or buccal mucous membrane,
and, if necessary, further adding desired carriers, vehicles, etc.
for preparations and making preparations in a conventional manner.
In addition, the preparation for transmucosal absorbing activity
may contain, for example, ether type non-ionic surfactants, enamine
derivatives of phenylglycine, N-acylcollagen peptides, sodium salts
of medium chain fatty acids, saponins, and so forth.
It is preferred that the percutaneous absorption accelerator of the
present invention be formulated, as the effective component, in an
amount of 0.001 to 10% by weight, particularly 0.1 to 8% by weight,
into the preparation for percutaneous administration, based on the
total amount of the preparation, as an aid for percutaneous
absorption. Further, in the case of using the percutaneous
absorption as the base for percutaneous absorption, it is also
possible to formulate the same in an amount of 10% by weight or
more.
Examples in which pharmaceutical effects increase by the
utilization of the percutaneous absorbent preparation of the
present invention as topical agents include steroid
anti-inflammatory agents, such as prednisolone, and dexamethason,
non-steroid anti-inflammatory agents, such as indomethacin,
fulfenamic acid, and mefenamic acid, anti-histamic agents, such a
tripernamine, insaibenzyl, chlorpheniramine, diphenhydramine, and
promethazine; sulfa agents, such as sulfamonomethoxine, and
sulfamethizole; and antibiotics, such as penicillin, cephalosporin,
erythromycin, tetracycline, chloramphenicol, and streptomycin;
anti-fungal agents, such as napthiomate, and clotrimazole;
anti-malignant tumor agents, such as 5-fluorouracil,
cyclophosphamide, busulfan, and actinomycin; analgesics, such as
morphine, codeine, nalorphine, pentazocine, aspirin, acetanilide,
and aminopyrine; preparations of prostaglandins; hypnotics and
tranquilizers, such as barbital, and thiopental; psychotropic
agents, such as chlorpromazine, reserpine, and chlordiazepoxide;
anti-epileptic agents; anti-Parkinson's syndrome agents, such as
chlorzoxazone, and levodopa; cardiotonic agents, such as digitoxin,
and digoxin; anti-arrhythmic agents, such as procainamide
hydrochloride, and propranolol hydrochloride; anti-angina pectoris
agents, such as dipyridamole, and amyl nitrite; anti-hypertension
agents, such as reserpine, and guanethidine sulfate; UV inhibitors,
such as p-aminobenzoate esters; agents for preventing the formation
of melanine, such as hydroquinone, vitamin C esters, and
p-hydroxycinnamate; PUVA treating agents against psoriasis, such as
8-methoxypsoralen; vitamins, such as vitamin A, estradiol, and
methyltestosterone; diagnostics; allergens for patch test;
vermicides, insecticides; moisturizers; keratin softening agents;
hair dyes; and the like, but are not exhaustive thereof.
Further, the percutaneous absorbent preparation for the topical
agent of the present invention is also effective for many drugs,
agricultural chemicals, growth hormones, etc. for which
pharmacological effects are expected by applying the same to
animals, insects, plants, and so on to be absorbed therein.
Examples in which pharmaceutical effects increase by the
utilization of the transmucosal absorption of the present invention
include pharmacologically active polysaccharide substances such as
heparin, dextran sulfate, pentosan sulfate (heparinoid),
chondroitin sulfate and salts thereof, glucoamylase inhibitor;
peptide type anti-tumor substances, such as bleomycin,
neocarzinostan, and L-asparginase; enzyme preparations, such as
trypsin, chemotrypsin, bromelain, papain, protenase, peroxidase,
nagase, proctase, serratiopeptidase, seaprose, lysozyme, plasmin,
urokinase, cytochrome C, hyaluronidase, fibrinolysine, thrombin,
callidin, callikrein, plasmin, glucose oxidase, B-galactosidase,
fytin, desoxyribonuclease, choline esterase, pronase, and
pancreatin; peptide hormones, such as calcitonin, parathormone,
relaxin, insulin, glucagon, prolactin, adrenocorticotropin (ACTH),
gonaotropic hormone, thyrotropin (TSH), growth hormone (BGH),
luteinizing hormone (LH), follicle-stimulating hormone (FSH),
oxytocin, vasopressin, anti-diuretic hormone, coherin,
melanocyte-stimulating hormone (MSH), gastrin, tetragastrin,
pentagastrin, secretin, pancreozymin, cholecystokinin, Substance P,
gonadotropin (HCG), and vasopressin; inhibitors for peptide hormone
releasing factors, such as adrenocorticotropic hormone releasing
factor (ACTH-RH), follicle-stimulating hormone releasing factor
(FSH-RH), growth hormone releasing factor (GH-IH), luteinizing
hormone releasing factor (LH-RH), prolactin releasing factor
(PR-RH), prolactin inhibiting factor (PR-IH), and
thyroid-stimulating hormone releasing factor (TSH-RH);
polynucleotides, such as polyribonucleotide, complex of
polyinocinic acid and cytidylic acid, complex of polyadenylic acid
and polyuridilic acid, and polydeoxyribonucleotide; insulin
secretion-activating protein (IAP), pancreas-basic trypsin
inhibitor, antipain hydrochloride, chymostatin A, elastatinal,
pepstatin A, polylysine, polyornithine, polyethylenimine, and
polyvinylamine; steroid anti-inflammatory agents, such as
prednisolone, and dexamethason; non-steroid anti-inflammatory
agents, such as indomethacin, fulfenamic acid, and mefenamic acid;
anti-histamic agents, such triperenamine, insaibenzyl,
chlorpheniramine, diphenhydramine, and promethazine; sulfa agents,
such as sulfamonomethoxine, and sulfamethizole; antibiotics, such
as penicillin, cephalosporin, erythromycin, tetracyclin,
chloramphenicol, and streptomycin; anti-malignant tumor agents,
such as 5-fluororacil, cyclophosphamide, bulsulfan, and
actinomycin; analgesics, such as morphine, codeine, nalophine,
pentazocine, aspirin, acetanilide, and aminopyrine; preparations of
prostaglandine; hypnotics and tranquilizers, such as barbital, and
thiopental; psychotropic agents, such as chlorpromazine, reserpine,
and chlordiazepoxide; anti-epileptic agents; anti-Parkinson's
syndrome agents, such as chlorzoxazone, and levodopa; cardiotonic
agents, such as digitoxin, and digoxin; anti-arrhythmic agents,
such as procainamide hydrochloride, and propranolol hydrochloride;
anti-angina pectoris agents, such as dipyridamole, and amyl
nitrite; and anti-hypertension agents, such as reserpine, and
guanethidine sulfate.
In the present percutaneous absorbent preparation, such a
pharmaceutically effective component may be incorporated in a
pharmaceutically effective amount according to the particular
object to which the preparation is to be applied.
In the ether derivative used in the present invention, the
structure can be appropriately chosen to control the balance
between a hydrophilic property and an oleophilic property so that
it is possible to prepare the ether derivative in any base having
either a hydrophilic or oleophilic property. As a result, the ether
derivative having a high solubility for various pharmaceutically
effective components can be chosen according to the present
invention. It is thus possible to design topical agents having good
handling and high percutaneous absorption by dissolving difficultly
soluble pharmaceutically effective components in hydrophilic bases
in a high concentration.
BRIEF DESCRIPTION OF DRAWING
FIG. 1 shows a change in blood concentration of salicylic acid when
the aspirin suppository of the present invention and the control
aspirin suppository containing no transmucosal absorption
accelerator were administered to rabbits.
PREFERRED EMBODIMENTS
Next, the present invention will be described with reference to the
examples below but it is not deemed to be limited only to these
examples.
TEST EXAMPLE 1
Japanese white male rabbits weighing about 2.5 kg, fasted for 24
hours, were fixed at the back, and each of solutions shown in Table
1 was administered to the rectum of about 2.5 cm from the anus
using a tube. Cannule was inserted into the femoral vein of the
hind leg to collect about 0.2 ml each of blood in every fixed time
interval. Blood sugar level was measured using dextrostix. Change
in blood sugar level was determined with the passage of time, as
the blood sugar level prior to administration being rendered 100%.
The results are shown in Table 1.
TABLE 1
__________________________________________________________________________
Rate of Change in Blood Sugar Level before Administration (%)
Specimen 15 mins. 30 mins. 45 mins. 60 mins. 90 mins. 120 mins.
__________________________________________________________________________
Control: Physiological saline 0.75 g +10.2 +12.5 +11.2 +11.2 +12.2
+18.0 Ethanol 0.25 g Insulin 10/kg 25% Ethanol solution +5.0 +12.9
+11.5 +4.8 +1.5 +2.7 1-O-n-Dodecyl-3-O-methyl- 1 g +6.5 +10.2 +9.8
+9.5 +9.5 +10.2 2-O-2',3'-dihydroxy- propylglycerol This
Physiological saline 0.70 g -13.4 -18.6 -25.2 -27.6 -25.8 -22.4
Inven- Ethanol 0.25 g tion Insulin 10/kg 1-O-n-Dodecyl-3-O-methyl-
2-O-2', 3'-dihydroxy- 0.05 g propylglycerol Physiological saline
0.65 g -19.2 -28.9 -32.7 -28.0 -19.5 -18.2 Ethanol 0.25 g Insulin
10/kg 1-O-n-Dodecyl-3-O-methyl- 0.1 g 2-O-2',3'-dihydroxypropyl-
glycerol 0.65 g -17.8 -18.3 -24.5 -28.6 -21.9 -19.8 Physiological
saline 0.25 g Ethanol 10/kg Insulin 0.1 g 1-O-Methyl-branched
isostearyl-3-O-methyl- 2-O-2',3'-dihydroxy- propylglycerol
__________________________________________________________________________
TEST EXAMPLE 2
To a mixture of 1.4 g of
1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol and 4.5 g
of ethanol was added a 17 U/ml insulin solution in physiological
saline and, the mixture was made 10 g in total to prepare a
preparation for nasal spraying. The preparation was administered to
the nasal cavity of male rabbits, weighing about 2.5 kg, fasted for
24 hours and fixed at the back, at a dose of 1 U/rabbit. Insulin in
serum was quantitatively determined by enzyme immunoassay. For
control, a preparation obtained by supplementing physiological
saline for the above-mentioned
1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol was used.
The results are shown in Table 2.
TABLE 2 ______________________________________ Concentration of
Insulin in Serum (uU/ml) 20 40 60 90 120 180 0 mins. mins. mins.
mins. mins. mins. ______________________________________ Control 5
8 12 12 12 14 14 This 7 261 227 95 78 31 28 Invention
______________________________________
EXAMPLE 1
Topical agents containing indomethacin shown below were prepared
and percutaneous absorption was examined with the topical agents.
The results are shown in Table 3.
PREPARATION
Preparation 1 of the present invention
An ointment obtained by incorporating 3 g of
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol into 97
g of a commercially available gel-like topical agent containing 1
wt % of indomethacin, Inteban ointment (made by Sumitomo Chemical
Industry Co., Ltd.).
Preparation 2 of the present invention
An ointment obtained by incorporating 3 g of 1-O-methyl-branched
isostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol into 97 g
of a commercially available gel-like topical agent containing 1 wt
% of indomethacin, Inteban ointment (made by Sumitomo Chemical
Industry Co., Ltd.).
Preparation 3 of the present invention
An ointment obtained by incorporating 3 g of 1-O-methyl-branched
isostearyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol into 97 g
of a commercially available gel-like topical agent containing 1 wt
% of indomethacin, Inteban ointment (made by Sumitomo Chemical
Industry Co., Ltd.).
Preparation 4 of the present invention
An ointment obtained by incorporating 3 g of
1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol into 97 g
of a commercially available gel-like topical agent containing 1 wt
% of indomethacin, Inteban ointment (made by Sumitomo Chemical
Industry Co., Ltd.).
Preparation 5 of the present invention
A liquid topical agent obtained by adding purified water to a
mixture of 1 g of indomethacin, 14 g of
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol and 45 g
of ethanol to make 100 g.
Preparation 6 of the present invention
A liquid topical agent obtained by adding purified water to a
mixture of 1 g of indomethacin, 14 g of 1-O-methyl-branched
isostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol and 45 g of
ethanol to make 100 g.
Preparation 7 of the present invention
A liquid topical agent obtained by adding purified water to a
mixture of 1 g of indomethacin, 14 g of 1-O-methyl-branched
isostearyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol and 45 g
of ethanol to make 100 g.
Preparation 8 of the present invention
A liquid topical agent obtained by adding purified water to a
mixture of 1 g of indomethacin, 14 g of
1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol and 45 g
of ethanol to make 100 g.
Comparative preparation 1
A commercially available gel-like topical agent containing 1 wt %
of indomethacin, Inteban.sup.R ointment (made by Sumitomo Chemical
Industry, Co., Ltd.).
Comparative preparation 2
A liquid topical agent obtained by adding purified water to a
mixture of 1 g of indomethacin, 14 g of N,N-diethyl-m-toluamide and
45 g of ethanol to make 100 g.
Comparative preparation 3
A liquid topical agent obtained by adding purified water to a
mixture of 1 g of indomethacin, 14 g of dimethylsulfoxide and 45 g
of ethanol to make 100 g.
Method:
Test of percutaneous absorption of indometacin
Seven (7) Japanese white female rabbits weighing about 3 kg were
used as one group. The topical agents of the present invention and
the comparative preparations were applied onto the normal abdominal
skin (10 cm.times.14 cm) of the rabbits in each group, from which
the body hair was cut, respectively, at a dose corresponding to 20
mg of indomethacin. Blood was collected from the vein of the ear
after 4, 10 and 20 hours and, blood concentration of indomethacin
was measured.
TABLE 3 ______________________________________ Maximum
Concentration in Preparation Serum (Cmax; ng/ml)
______________________________________ This invention 1 540 This
invention 2 510 This invention 3 500 This invention 4 420
Comparative 1 95 Preparation This invention 5 1900 This invention 6
1750 This invention 7 1550 This invention 8 1230 Comparative 2 190
Preparation Comparative 3 150 Preparation
______________________________________
As is clear from the results described above, topical agents 1 to 8
of the present invention all showed extremely high percutaneous
absorption of indomethacin as compared to the comparative
preparations. In particular, the topical agent of the present
invention obtained by formulating
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol as a
percutaneous absorption accelerator showed extremely high
percutaneous absorption of indomethacin.
EXAMPLE 2
With respect to the topical agents of the present invention, the
pharmacological effect was examined according to the inhibition of
carrageenin caused edema on the paw of the rat. The results are
shown in Table 4.
Method
Wistar male 10 rats, weighing about 110 g, were used as one group.
The volume of the right rear paw of the rats in each group was
previously measured using a branched glass container. A 1%
carrageenin aqueous solution was subcutaneously injected to the
right rear paw sole in a dose of 0.125 ml. Immediately thereafter
0.3 g of indomethacin topical agents were applied to the skin of
the right rear paw sole. In the control group, carrageenin alone
was injected. Then, the volume of the rear paw was measured every
90 minutes, which was continued until 6 hours after. The rate of
edema and the inhibition rate of edema were calculated as described
below. ##EQU1##
TABLE 4 ______________________________________ Inhibition Rate of
Edema (%) Preparation 1.5 hr 3.0 hrs 4.5 hrs 6.0 hrs
______________________________________ This invention 5 52.6 52.7
53.7 56.0 This invention 8 23.7 37.4 40.8 50.3 Comparative 1 10.5
3.9 3.5 2.0 Preparation ______________________________________
As is clear from the results described above, the topical agents of
the present invention showed an extremely high rate of preventing
the edema caused by carrageenin due to the pharmacological effect
of indomethacin, as compared to the comparative preparation. In
particular, the topical agent obtained by formulating
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol as a
percutaneous absorption accelerator showed an extremely high
pharmacological effect of indomethacin.
EXAMPLE 3
A topical agent containing mefenamic acid shown below was prepared
and the percutaneous absorption was tested. The results are shown
in Table 5.
Preparation 9 of the present invention:
Mefenamic acid, 1 g, was incorporated in a mixture of 10 g of
propylene glycol, 5 g of
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol and 30 g
of ethanol. The mixture was added to a swollen mixture of 1 g of
"HIVISWAKO-104" (made by Wako Pure Chemical Industries, Ltd.,
carboxymethyl polymer) in 20 g of purified water. After the mixture
was homogeneously mixed, 3 g of 2% ammonia water was added thereto
while stirring and, purified water was further added thereto to
make 100 g to obtain a gel ointment.
Comparative preparation 4
Mefenamic acid, 1 g, was incorporated in a mixture of 15 g of
propylene glycol and 30 g of ethanol. The mixture was added to a
swollen mixture of 1 g of "HIVISWAKO-104" (made by Wako Pure
Chemical Industries, Ltd., carboxymethyl polymer) in 20 g of
purified water. After the mixture was homogeneously mixed, 3 g of
2% ammonia water was added thereto while stirring and, purified
water was further added thereto to make 100 g to obtain a gel
ointment.
Method
Test for percutaneous absorption of mefenamic acid
Seven (7) Japanese white female rabbits weighing about 3 kg were
used as one group. The topical agents of the present invention and
the comparative preparations were applied onto the normal abdominal
skin (10 cm.times.14 cm) of the rabbits in each group, from which
the body hair was cut, respectively, at a dose corresponding to 50
mg of mefenamic acid. Blood was collected from the vein of the ear
after 4, 10 and 20 hours and, blood concentration of mefenamic acid
was measured.
TABLE 5 ______________________________________ Concentration of
Mefenamic Acid in Serum (C; .mu.g/ml) Preparation 4 hrs 10 hrs 20
hrs ______________________________________ This invention 9 4.9 5.1
4.7 Comparative 1.8 1.1 0.4 Preparation
______________________________________
As is clear from the results described above, the topical agent of
the present invention showed extremely high percutaneous absorption
of mefenamic acid, as compared to the comparative preparation.
EXAMPLE 4
Cataplasms shown below were prepared and, the percutaneous
absorption of methyl salicylate was tested. The results are shown
in Table 6.
Preparation
Preparation 10 of the present invention
To 10 parts (weight basis, hereafter the same) of gelatin were
added 35 parts of water. The mixture was warmed to 70.degree. C. to
dissolve gelatin therein. To this solution were added 12 parts of
titanium oxide, 10 parts of glycerol, 10 parts of sorbitol and 10
parts of
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol. Then, 5
parts of self-cross linkable sodium polyacrylate (prepared in
accordance with Example 1 of Published Examined Japanese Patent
Application No. 30710/79) and 5 parts of sodium carboxymethyl
cellulose were added to the mixture. Further 3 parts of a drug
(drug mixture obtained by formulating 1-menthol, d-camphor and
methyl salicylate in a weight ratio of 5:1:4) were added thereto
and the mixture was kneaded to obtain a cataplasm paste
composition. The composition was coated on a lint sheet. A
polypropylene film was applied to the paste surface, which was cut
into an appropriate size to obtain a cataplasm.
Preparation 11 of the present invention
A cataplasm similar to Preparation 10 of the present invention was
prepared by formulating 10 parts of 1-O-methyl-branched
isostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol instead of
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol in
Preparation 10 of the present invention, 10 parts of glycerol and
10 parts of sorbitol.
Comparative preparation 5
A cataplasm similar to Preparation 10 of the present invention was
obtained except that 15 parts of glycerol and 15 parts of sorbitol
were used in place of 10 parts of glycerol and 10 parts of
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol.
Method
Test for percutaneous absorption of methyl salicylate
Seven (7) Japanese white female rabbits weighing about 3 kg were
used as one group. Each sheet of the cataplasms of the present
invention and the comparative preparation, in which 1.2 wt % of
methyl salicylate was formulated, were applied to the normal
abdominal skin (10 cm.times.14 cm) of the rabbits in each group,
from which the body hair was cut, respectively. Blood was collected
from the vein of the femur after 3, 6, 10, 20 and 30 hours and,
blood concentration of methyl salicylate was measured.
TABLE 6 ______________________________________ Maximum Concent-
ration in Serum Reaching Time Preparation (Cmax; .mu.g/ml) (Tmax;
hr) ______________________________________ This invention 10 47 10
This invention 11 41 10 Comparative 5 14 6 Preparation
______________________________________
As is clear from the results above, the cataplasms of the present
invention all showed extremely high percutaneous absorption of
methyl salicylate, as compared to the cataplasm for comparison. In
particular, the cataplasm of the present invention obtained by
formulating
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol as the
percutaneous absorption accelerator showed extremely high
percutaneous absorption of methyl salicylate.
EXAMPLE 5
Topical agents containing naphthiomate shown below were prepared
and, the percutaneous absorption was tested. The results are shown
in Table 7.
Preparation
Preparation 12 of the present invention
A mixture of 1 g of naphthiomate, 5 g of
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol, 14 g of
glycerol triacetate 30 g of methyl ethyl ketone and 50 g of ethanol
was made a liquid topical agent.
Comparative preparation 6
A mixture of 1 g of naphthiomate, 19 g of glycerol triacetate 30 g
of methyl ethyl ketone and 50 g of ethanol was made a liquid
topical agent.
Method
Test for percutaneous absorption of naphthiomate
Wistar-strain male 10 rats, weighing about 150 g, were used as 1
group. The topical agent was applied to the normal back skin (5
cm.times.4 cm) of the rats of each group, from which the body hair
was cut, in a dose corresponding to 2 mg of naphthiomate. Blood was
collected from the abdominal main artery after 10 hours and, blood
concentration of naphthiomate was measured.
TABLE 7 ______________________________________ Concentration of
naphthiomate Preparation in serum (C; ng/ml)
______________________________________ This invention 12 29.5
Comparative 6 9.3 Preparation
______________________________________
As is clear from the results described above, the topical agent
prepared in the example showed extremely high percutaneous
absorption of naphthiomate, as compared to the comparative
example.
EXAMPLE 6
Aspirin Suppository
______________________________________ (1) Pharmacopeial aspirin 1
g (2) 1-O-n-Dodecyl-3-O-methyl- 0.5 g 2-O-2',3'-dihydroxypropyl-
glycerol (3) Homotex (made by Kao Soap Co., 8.5 g Ltd.; medium
chain fatty acid triglyceride)
______________________________________
(1) to (3) were thoroughly agitated and mixed and, 1 g each of the
mixture was filled up in a soft gelatin capsule to prepare an
aspirin suppository.
The aspirin suppository of Example 6 was administered to male
rabbits weighing about 3 kg and, change in blood concentration of
salicylic acid was measured. For control, the following was
used.
Control: suppository containing 100 mg of pharmacopeial aspirin in
Homotex as a base.
The results are shown in FIG. 1.
EXAMPLE 7
Indomethacin Suppository
______________________________________ (1) Pharmacopeial
indomethacin 1.5 g (2) 1-O-Methyl-branched isostearyl- 0.5 g
3-O-methyl-2-O-2',3'-dihydroxy- propylglycerol (3) Homotex (supra)
8.0 g ______________________________________
(1) to (3) were thoroughly agitated and mixed and, 1 g each of the
mixture was filled up in a soft gelatin capsule to prepare an
indomethacin suppository.
EXAMPLE 8
In a manner similar to Example 6, an aspirin suppository was
prepared using
1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol.
EXAMPLE 9
In a manner similar to Example 7, and indomethacin suppository was
prepared using
1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol.
EXAMPLE 10
Insulin Suppository
______________________________________ (1) Solution of 100 IU of
0.5 g insulin in 0.5 ml of a 6% aqueous acetic acid solution (2)
1-O-n-Dodecyl-3-O-methyl- 0.5 g 2-O-2',3'-dihydroxypropyl- glycerol
(3) Homotex 9.0 g ______________________________________
After (1) to (3) were thoroughly agitated to disperse, 1 g each of
the dispersion was filled up in a soft gelatin capsule to prepare
an insulin suppository.
EXAMPLE 11
Insulin Spraying Agent for Nasal Use
______________________________________ (1) Solution of 1000 IU of 2
g insulin in 2.0 ml of a 6% aqueous acetic acid solution (2)
1-O-Methyl-branched 2 g isostearyl-3-O-methyl- 2-O-2'3-dihydroxy-
propylglycerol (3) Ethanol 6 g (4) Physiological saline solu- 90 g
tion ______________________________________
(1) to (4) were thoroughly mixed, and, the mixture was filled up in
a pump sprayer to make an insulin spraying agent for nasal use.
The invention being thus described, it will be obvious that the
same may be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the invention,
and all such modifications as would be obvious to one skilled in
the art are intended to be included within the scope of the
following claims.
* * * * *